Evaluation of MSP Antagonists for the Treatment of Pancreatic Cancer

Summary

Principal Investigator: Joseph W Harding
Abstract: DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States. Effective treatment strategies have been elusive as evidenced by typical survival times after diagnosis of <1 year. Pancreatic cancer is characterized clinically by its aggressive metastatic activity and resistance to typical cytotoxic chemotherapeutic agents. Recent studies have implicated the over activation of two growth factor systems macrophage stimulating protein(MSP)/RON (its receptor) and hepatocyte growth factor(HGF)/c- Met(its receptor) as critical contributors to pancreatic cancer's ability to disseminate rapidly and its refractoriness to standard chemotherapy. Thus, the objectives of this project are to develop small molecule MSP antagonists and/or dual acting MSP/HGF antagonists that target the dimerization/activation domain of MSP and MSP/HGF for use as pancreatic cancer therapeutics. To reach these objectives the following specific aims will be addressed. 1) Establish that Macrophage-Stimulating protein (MSP) dimerizes. Demonstrate that a peptide representing the putative dimerization domain of MSP (KDYVRT) can block dimerization. 2) Demonstrate that KDYVRT can inhibit the ability of MSP to activate its receptor, RON, and downstream targets by monitoring its effects on MSP-dependent RON, Gab1, akt, and ERK phosphorylation in HEK293 cells. Further demonstrate that KDYVRT can inhibit MSP-dependent effects on HEK293 migration and proliferation. 3) Evaluate the potential of KDYVRT and related molecules to act as dual MSP/HGF antagonists by assessing the ability of KDYVRT and related molecules to concomitantly inhibit HGF-dependent c-Met activation and HGF-dependent cellular responses in HEK293 cells. 4) Demonstrate that KDYVRT can inhibit the growth and survival of MSP/RON and HGF/c-Met sensitive BxPC3 human pancreatic cancer cells as assessed by fluorescent cell sorting methods. 5) Demonstrate that KDYVRT can suppress the growth and metastasis of BxPC3-luc2 human pancreatic cancer cells in an orthotopic NOD-SCID model using live in vivo imaging methodologies and evaluate the effect of KDYVRT on RON and c-Met activation within the tumors. And, 6) Assuming that KDYVRT is effective at blocking RON activation, a limited number of prototype peptides and peptidomimetic will be synthesized that have improved pharmacokinetic properties. Success of these feasibility studies will spur the synthesis of new dimerization domain based molecules with improved pharmacokinetic properties and better bioavailability. Continued success of the development program should lead to the identification of a lead molecule(s), which would be expected to enter clinical development.
Funding Period: 2013-04-01 - 2015-03-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. FoxM1: A molecular target in pancreatic cancer
    Fazlul H Sarkar; Fiscal Year: 2013
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  2. Targeting STAT3 as a novel approach to cancer therapy
    Said M Sebti; Fiscal Year: 2013
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  3. Combination therapy to inhibit neuroblastoma growth
    CHRISTOPHER SUMEET BABU GONDI; Fiscal Year: 2013
    ..This proposal represents a comprehensive analysis to determine the therapeutic benefit of SPARC expression in combination with radiation for the treatment of neuroblastoma. ..
  4. Novel Nanoparticle Therapy for Pancreatic Cancer
    Mark Kester; Fiscal Year: 2013
    ..Our long term goal is to develop novel effective strategies to improve therapy and survival of patients with this devastating malignancy. ..
  5. The Role of Cyr61 in Patho-Biology and Therapeutics of Pancreatic Cancer
    Snigdha Banerjee; Fiscal Year: 2013
    ..The role of Cyr61 in resistance to chemotherapy will also be evaluated. We are anticipating that the outcome of these studies will propose that targeting Cyr61 can provide a new treatment option for patients with pancreatic cancer. ..
  6. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
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  7. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..